The present invention is related to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.
The xcex4 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the xcex4 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the xcex4 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (xcexc, xcex4 and xcexa) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid xcex4 ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic xcex4 antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e.,  less than 10-fold) selectivity for the xcex4 receptor vs. xcexc receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic xcex4 ligands.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current xcexc agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
The problem mentioned above has now been solved by developing novel 1,4-substituted phenyl compounds, as will be described below.
The novel compounds according to the present invention are defined by the general formula I 
wherein
m and n is each and independently an integer of from 1-3, and one or more of the hydrogens in such an alkylene-chain may optionally be substituted by anyone of C1-C6 alkyl, C1-C6 alkoxy, or hydroxy, or
one or more of the methylene groups may optionally be substituted by a heteroatom such as O, N or S;
R1 is selected from hydrogen, a branched or straight C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C4-C8(alkyl-cycloalkyl) wherein the alkyl is C1-C2 alkyl and the cycloalkyl is C3-C6 cycloalkyl;
R2 is selected from any of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) xe2x80x94[(CH2)q-aryl];
(iv) xe2x80x94[(CH2)r-heteroaryl] where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; and wherein q and r is each and independently an integer of from 0 to 3;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; or
R1 and R2 may optionally form a heterocyclic ring;
R3 is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) xe2x80x94[(CH2)q-aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) xe2x80x94[(C3-C6 cycloalkyl)-CH2)q] wherein q is an integer of from 1 to 3;
R4 is selected from
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) xe2x80x94[(CH2)q-aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteroaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(vi) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
R5 is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(iii) xe2x80x94[(CH2)q-aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(iv) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; 
xe2x80x83wherein
R7, R8, R9, R10 and R11 is each and independently selected from
(a) hydrogen;
(b) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(c) xe2x80x94[(CH2)q-aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
(d) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(e) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(f) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; or
R4 and R5 may optionally form a heterocyclic ring;
Y is each and independently selected from any of hydrogen, CH3; xe2x80x94(CH2)p1CF3; halogen; C1-C3 alkoxy; hydroxy; xe2x80x94NO2; xe2x80x94OCF3; xe2x80x94CONRaRb; xe2x80x94COORa; xe2x80x94CORa; xe2x80x94(CH2)p2NRaRb; xe2x80x94(CH2)p3CH3, (CH2)p4SORaRb; xe2x80x94(CH2)p5SO2Ra; xe2x80x94(CH2)p6SO2NRa; C4-C8(alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; 1 or 2 heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O; and oxides such as N-oxides or sulfoxides; and wherein
Ra and Rb is each and independently selected from hydrogen, a branched or straight C1-C6 alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl; and wherein
p1, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula I, as well as isomers, hydrates, isoforms and prodrugs thereof.
Examples of heterocyclic ring systems which may be formed by R2 and R3 together include but are not limited to azeridine, pyrrolidine, piperidine, azepine, azocine, their hydrogenated or dehydrogenated derivatives, their aminoderivatives and other aza-heterocycle moieties and their derivatives, such as dihydroimidazoles, di-, tetra- and hexahydropyrimidines and the like.
Preferred compounds according to the invention are compounds of the formula I wherein
m=n=1
R1 is selected from
(i) hydrogen;
(ii) a branched or straight C1-C6 alkyl; or
(iii) C3-C8 cycloalkyl;
R2 is selected from any of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
(iii) xe2x80x94[(CH2)q-aryl];
(iv) xe2x80x94[(CH2)r-heteroaryl] where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; and wherein q and r is each and independently an integer of from 0 to 3;
(v) C3-C6 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(vi) C6-C10 aryl, optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; or
R1 and R2 may optionally form a heterocyclic ring;
R3 is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
(iii) xe2x80x94[(CH2)q-aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(iv) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(vi) xe2x80x94[(C3-C6 cycloalkyl)-(CH2)q] wherein q is an integer of from 1 to 3;
R4 is selected from
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
(iii) xe2x80x94[(CH2)q-aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(iv) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(v) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
R5 is selected from anyone of
(i) hydrogen;
(ii) a straight or branched C1-C6 alkyl;
(iii) xe2x80x94[(CH2)q-aryl] wherein q is 0 or 1, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(iv) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(v) C3-C6 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; 
xe2x80x83wherein
R7, R8, R9, R10 and R11 is each and independently selected from
(a) hydrogen;
(b) a straight or branched C1-C6 alkyl or C2-C6 alkenyl;
(c) xe2x80x94[(CH2)q-aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
(d) heteoaryl-(C5-C10 alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(e) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(f) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; or
R4 and R5 may form a heterocyclic ring which may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above.
Particularly preferred compounds according to the invention are compounds of the formula I wherein
m=n=1
R1 is selected from
(i) a straight or branched C1-C6 alkyl; or
(ii) C3-C8 cycloalkyl;
R2 is selected from
(i) methyl; or
(ii) phenyl optionally substituted by 1 or 2 substituents Y wherein each Y is as defined above;
R3 is selected from
(i) xe2x80x94CH2-phenyl, optionally substituted by 1 or 2 substituents Y where Y is as defined above;
(ii) xe2x80x94CH2-cyclohexyl or xe2x80x94CH2-cyclopentyl;
R4 is selected from
(i) hydrogen; or
(ii) methyl;
R5 is selected from
(i) hydrogen;
(ii) methyl; or 
xe2x80x83or
R4 and R5 together form a heterocyclic ring, optionally substituted by 1 or 2 substituents Y, where Y is as defined above.
By xe2x80x9chalogenxe2x80x9d we mean chloro, fluoro, bromo and iodo.
By xe2x80x9carylxe2x80x9d we mean an aromatic ring having 6 or 10 carbon atoms, such as phenyl and naphthyl.
By xe2x80x9cheteroarylxe2x80x9d we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By xe2x80x9cisomersxe2x80x9d we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By xe2x80x9corientationxe2x80x9d we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By xe2x80x9cisoformsxe2x80x9d we mean compounds of the formula I which differ in the relative physical arrangement of molecules by crystal lattice, such that isoforms refer to various crystalline compounds and amorphous compounds.
By xe2x80x9cprodrugxe2x80x9d we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is an active form of the drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated by reference.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastrointestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. Amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids.
The compounds of the present invention in isotopically labelled form are useful as a diagnostic agent.
Also within the scope of the invention is the use of any of the compounds according to the formula (I) above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula (I) above, is administered to a patient in need of such treatment.
The best mode of performing the invention known at present, is to use the compounds according to Example 1 (compound 12) and Example 2 (compound 13). The numbering of the compounds is in accordance with the numbering in the Schemes presented in the following.
The compounds of the present invention may be prepared as described in Scheme 1 below.

As shown in Scheme 1 above, compounds of the formula VI may be obtained from commercially available bis-amino xylylene (compound 1).
Compound 1 is converted into mono-(diBoc)-guanidinomethyl derivative 2 using a protected guanylating reagent such as 1-H-pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine in an organic solvent such as THF.
The secondary amine of the formula III may be generated using a reductive amination step, where compound 2 is reacted with an aldehyde II in the presence of an acid such as acetic acid or a Lewis acid such as ZnCl2, in a protic solvent such as methanol or ethanol in the presence of a reducing agent such as sodium cyanobrohydride.
Compounds of the formula V may be obtained by performing an urea formation using compound III with a chloroformate of the formula IV in a solvent such as methylene chloride and in the presence of a tertiary amine as base, such as triethylamine.
Finally, a compound of the formula VI may be obtained by cleavage of the Boc protecting group with an acid such as aqueous hydrochloric acid or by using organic acid such as trifluoroacetic acid in a solvent such a methylene chloride.
The invention will now be described in more detail by way of the following Examples, which are not to be construed as limiting the invention in any way.
Step 1 (a)
Part A
1-H-pyrazole-1-carboxamidine was prepared according to Bernatowicz et.al., J. Org. Chem. 1992, 57, pp.2497-2502, and protected with di-tert-butyl dicarbonate to give 1-H-pyrazole-1-N,N-bis(tert-butoxycarbonyl)carboxamidine (compound 1) according to Drake et.al, Synth. 1994. pp.579-582.
Part B
To a solution of p-xylylenediamine (compound 1) (30.8 g, 0.226 mol) in THF (300 mL) was added a solution of 1-H-Pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine (35.0 g, 0.113 mol) in THF (100 mL). The solution was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. Water was added to the residue and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product (compound 2) was purified by column chromatography on silica gel using a mixture of methylene chloride:methanol as the eluent to give 24.3 g (57% yield) of 1-(diBoc)-guanidinomethyl-4-aminomethyl benzene (compound 2 where NH2 is in 4-position).
1H NMR (CDCl3) xcex48.5 (broad s, 1H), 7.32 (s, 4H), 4.65 (d, 2H), 3.89 (s, 2H), 1.5 (s, 9H), 1.48 (s, 9H).
Step 1 (b)
1-(diBoc)-guanidinomethyl-3-aminomethyl benzene was prepared in a similar fashion from m-xylylenediamine and of 1-H-pyrazole-1-(N,N-bis(tert-butoxycarbonyl)carboxamidine.
1H NMR (CDCl3) xcex48.52 (broad s, 1H), 7.28-7.08 (m, 4H), 4.56 (d, 2H), 3.81 (s, 2H), 1.42 (s, 9H), 1.39 (s, 9H).
Step 2
To a methanolic solution (15 ml) of compound 2 where the amino group is in 4-position) (341 mg, 0.90 mmol) and cyclohexanecarboxaldehyde (111.17 mg, 0.99 mmol) was added zinc chloride (122.79 mg, 0.90 mmol) and sodium cyanoborohydride (67.93 mg, 1.08 mmol). The mixture was stirred over night under nitrogen, wherafter the mixture was diluted with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO4 and concentrated. This crude product was further purified by silica gel chromatography using CH2Cl2/MeOH (95:5) as the solvent, to give 164 mg of the pure desired product (compound 2 where NH2 is in 3-position).
1H NMR (CDCl3) xcex4 (ppm): 0.83 (2H, m, cyclohexane ring); 1.10 (3 H, m, cyclohexane ring); 1.42 (9H, s, boc), 1.46 (9H, s, boc), 1.65 (6H, m, cyclohexane ring), 2.41 (2H, d, J=6.8 Hz, C6H11xe2x80x94CH2), 3.72 (2H, s, C6H4xe2x80x94CH2), 4.54 (2H, d, J=5.6 Hz, NNCNHxe2x80x94CH2xe2x80x94C6H4), 7.18-7.25 (4H, m, Ar), 8.50 (1H, br, NHxe2x80x94CNN) ppm.
Specific examples illustrating the preparation of secondary amines, i.e. intermediates of the formula III, are provided in Table 1 below.

Alternatively, as shown in Scheme 2, compounds of the formula (XI) may be obtained by using compounds of the formula (VIII) wherein X=CN and Y=CHO, as a starting material.
A reductive amination using a primary amine with compound (VIII) in the presence of an acid such as acetic acid, and in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as methanol or ethanol, provides a compound of the formula (IX).
Compounds of the formula (X) may be obtained by performing an urea reaction using compounds of the formula (IX) with a chloroformate of the formula (V) in a solvent such as methylene chloride and in the presence of a tertiary amine as base, such as triethylamine.
Compounds of the formula (XI) may be prepared by a reduction of the nitrile function in formula (X), using a reduction agent such as borane-THF complex in a solvent such as THF.
Compounds of the formula (XV) may be prepared by reacting compounds of the formula (VIII) wherein X=CH2Br and Y=CN, with an amine in a solvent such as acetonitrile, providing a compound of the formula (XII). A reduction of the nitrile function using a reducing agent such as borane-THF complex in a solvent such as THF, provides the primary amine of the formula (XIII).
A reductive amination step of (XIII) as described above, provides a compound of the formula (XIV). Finally, urea formation of the secondary amine (XIV) as described above, provides a compound of the formula (XV).
Alternatively, compounds of the formula (XV) may be prepared by using a monoprotected dialdehyde such as a compound of the formula (VIII) wherein X=CH(OEt)2 and Y=CHO, and a reductive amination in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as methanol or ethanol. Urea formation as described above provides a compound of the formula (XVII). Hydrolysis of the diethyl acetal function in compound (XVII) using an acid such as TFA in a solvent such as methylene chloride, provides the corresponding aldehyde (XVIII).
Finally, a reductive amination as described before, provides compounds of the formula (XV).